STAT3 in T helper cell development

STAT3 在 T 辅助细胞发育中的作用

• 批准号: 8461515
• 负责人: MARK H KAPLAN
• 金额: $ 7.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461515
• 关键词: Allergic Disease; Antibody Formation; Asthma; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Bacteria; Binding; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Characteristics; Complex; Cytokine Signaling; Data; Development; Disease; Gene Targeting; Genes; Genetic Programming; Goals; Helper-Inducer T-Lymphocyte; Hypersensitivity; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Mycoses; Parasites; Phenotype; Process; Production; Proteins; Role; STAT protein; STAT3 gene; STAT4 gene; STAT6 gene; Signal Transduction; T-Lymphocyte Subsets; Testing; base; chromatin immunoprecipitation; cytokine; extracellular; genome-wide; in vivo; pathogen; programs; promoter; research study; response; transcription factor

DESCRIPTION (provided by applicant): CD4+ T helper cells are central regulators of adaptive immune responses. CD4+ T helper cells differentiate into several distinct subsets to provide host protection against a variety of pathogens. Each T helper cell lineage expresses characteristic transcription factors and cytokines that confer specific effector functions. The cytokine-secreting potential of effector T helper subsets requires the activation and expression of transcription factors that promote the development of each subset. Differentiation is stimulated by the cytokine microenvironment and the activation of Signal Transducer and Activator of Transcription (STAT) proteins that initiate specific genetic programs. A simple paradigm suggested the requirement for a single STAT protein activated by a cytokine that promoted the development of a specific T helper subset. However, developing Th subsets are exposed to multiple cytokines. We have recently provided evidence that the ability of Th cells to integrate signals from multiple cytokines is necessary for optimal subset development. Specifically, we demonstrated that STAT3, which clearly promotes Th17 development in isolation, promotes Th2 differentiation when it cooperates with STAT6 in programming Th2 cytokine expression by binding to many of the same loci as STAT6. In this proposal we test the hypothesis that STAT3 binds to common and unique genes among Th subsets by using chromatin immunoprecipitation and massive parallel sequencing to define the targets of STAT3 in multiple T cell subsets. These studies will define how a developing Th cell integrates multiple signals at the level of transcription factor binding and provide the basis for a new paradigm wherein a single STAT may be the key to a particular phenotype, whereas other STAT proteins cooperate to achieve optimal differentiation and ultimately immune responses.

描述（由申请人提供）：CD4+ T辅助细胞是适应性免疫反应的中心调节剂。 CD4+ T辅助细胞分化为几个不同的子集，以防止各种病原体提供宿主保护。每个T辅助细胞谱系都表达具有特定效应子功能的特征转录因子和细胞因子。效应助手亚基的细胞因子分泌潜力需要促进每个子集发育的转录因子的激活和表达。细胞因子微环境以及启动特定遗传程序的转录（Stat）蛋白的激活和激活的激活来刺激分化。一个简单的范式表明，对促进特定T助手子集发育的细胞因子激活的单个Stat蛋白的要求。但是，开发子集暴露于多种细胞因子。我们最近提供了证据，表明TH细胞从多种细胞因子中整合信号的能力对于最佳亚集群开发是必要的。具体而言，我们证明了STAT3清楚地促进了Th17孤立的发展，它通过与STAT6与许多相同的基因座结合在编程Th2细胞因子表达中与STAT6合作时促进了Th2的分化。在此提案中，我们通过使用染色质免疫沉淀和大规模平行测序来定义多个T细胞子集中的STAT3靶标的STAT3与TH子集中的常见基因结合的假设。这些研究将定义开发的细胞如何在转录因子结合的水平上整合多个信号，并为新范式提供基础，其中单个统计数据可能是特定表型的关键，而其他STAT蛋白会合作以实现最佳分化并最终获得免疫反应。